CYCLOOXYGENASE-2 EXPRESSION BY ENDOTHELIN-1-STIMULATED MOUSE RESIDENTPERITONEAL-MACROPHAGES IN-VITRO

Macrophages have been shown to produce endothelin and to play a role i n the pathogenesis of neural damage after cerebral ischemia or vasospa sm after subarachnoid hemorrhage. Cyclooxygenase 2 is induced during i nflammation following brain insult and participates in inflammation-me diate neurotoxicity. However, it has not yet been established how endo thelin-1 acts on cyclooxygenase 2 expression in macrophages. In the pr esent study, we examined the effects of endothelin-1 on cyclooxygenase 2 expression and prostaglandin E-2 production, and the effects of end othelin ETA and ETB receptor antagonists. Stimulation by endothelin-1 ranging from 10(-11) to 10(-9) M time and dose dependently increased t he production of prostaglandin E-2 and the expression of cyclooxygenas e 2 protein without changing that of cyclooxygenase 1 protein, an effe ct which was inhibited by dexamethasone, nonsteroidal anti-inflammator y drugs and the selective endothelin ETB receptor antagonist, BQ788 yl -D-L-methoxycarbonyl-tryptophanyl-D-norleucine). the selective endothe lin ETA receptor antagonist, BQ123 [cyclo (o-Trp-D-Asp-Pro-D-Val-Leu)] also inhibited these reactions, but its potency was less than that of the selective endothelin ETB receptor antagonist. Endothelin ETA and ETB receptor antagonists had no effects on cyclooxygenase 2 protein ex pression and prostaglandin E-2 production in lipopolysaccharide-stimul ated macrophages. We conclude that endothelin-1 increases cyclooxygena se 2 protein expression and prostaglandin E-2 production via mainly en dothelin ETB receptors and partly endothelin ETA receptors in macropha ges; however, lipopolysaccharide increases both cyclooxy genase 2 prot ein expression and prostaglandin E-2 production in pacrophages without involving endothelin ETA or ETB receptor-mediated processes. (C) 1998 Elsevier Science B.V. All rights reserved.